This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The goal of this proposal is to identify the effects of prion infection on replication of a subsequently inoculated second prion strain. Prior inoculation of rodents with a long incubation prion strain can delay the incubation period or block a subsequently inoculated (i.e. superinfected) short incubation prion strain, however, the location and cell types in the CNS where prion strain selection occur are not known. Investigation of the mechanisms responsible for the inhibition of the superinfected prion strain replication may lead to identification of host factors involved in prion replication. The hypothesis to be tested is that prion infection of neurons inhibits subsequent prion infection and/or replication of another prion strain. To test this hypothesis, the sciatic nerve model of prion strain targeting and competition will be utilized. In this model of prion disease, prions are transported to the brain along three motor spinal tracts. Inoculation of the sciatic nerve with the long incubation period drowsy strain of hamster-adapted TME (DY TME) 120 days prior to sciatic nerve inoculation with the short incubation period hyper TME (HY TME) strain can block HY TME and results in DY TME. The sciatic nerve model of prion strain selection can facilitate the identification of the areas and cell types involved in prion strain selection.